The role of the immune system is to protect the body from pathogens and malignant cells. However, viruses and cancer cells find ways to evade the immune system. The aim of immunotherapies is thus to initiate an antigen specific immune response or to re-activate a pre-existing response in certain cell types of the immune system against the pathogenic invaders or cancerous cells.
The immune system consists of several specialized lineages which can be roughly grouped into two arms, the innate and the adaptive immune system. For a successful immune reaction, lineages from both arms have to act in concert. A major role of the innate immune system is to mount a rapid immune response against pathogens or malignant cells which, unlike the adaptive system, is not antigen specific and long lasting. In addition to the direct killing of pathogens or transformed cells, the innate immune system also activates and subsequently directs the adaptive immune system. Antigen presenting cells such as dendritic cells capture and present antigens in the form of a peptide-major histocompatibility complex (MHC) complex to T cells in lymphoid tissues. This antigen presentation together with the secretion of certain cytokines leads to the activation and differentiation of antigen specific effector CD4 and CD8 T cells. Type I interferon (IFN) production by antigen presenting cells, and other cell types, is considered a key event in the activation of T cells as the lack of type I IFN resulted in a reduced T cell dependent immune response against viral infections or tumor cells (Zitvogel et al, Nature Reviews Immunology 15, 405-414, 2015). On the other hand, the presence of a type I IFN signature during cancer therapy is associated with increased numbers of tumor infiltrating T cells and potentially favorable clinical outcome (Sistigu et al, Nature Medicine 20, 1301-1309, 2014). Recent studies in mice have shown that efficient secretion of type I IFN in the tumor microenvironment and the induction of a T cell dependent immune response against cancer cells depends on the presence of the adaptor protein stimulator of interferon genes (STING, also known as Tmem173, MPYS, MITA, ERIS) (Woo et al, Immunity 41, 5, 830-842, 2014; Corrales et al, Cell Reports 11, 1018-1030, 2015; Deng et al, Immunity 41, 5, 843-852, 2014). The importance of the presence of type I IFN was highlighted by the fact that the deletion of STING resulted in reduced type I IFN levels in the tumor microenvironment and in a reduced anti-tumor effect in several mouse tumor models. On the other hand, the specific activation of STING resulted in an improved, antigen specific T cell immune response against cancer cells.
STING belongs to the family of nucleic acid sensors and is the adaptor for cytosolic DNA signaling. In its basal state STING exists as a dimer with its N terminal domain anchored in the ER and the C-terminal domain residing in the cytosol. Cyclic dinucleotides (CDNs), generated by the protein cyclic GMP-AMP Synthase (cGAS) are the natural ligands of STING (Ablasser et al, Nature 498, 380-384, 2013). Binding of CDNs to STING induces conformational changes which allows the binding and activation of the TANK binding kinase (TBK1) and interferon regulatory factor 3 (IRF3) and the relocalisation from the ER to perinuclear endosomes (Liu et al, Science 347, Issue 6227, 2630-1-2630-14, 2015). Phosphorylation of the transcription factor IRF3 and NF-kB by TBK1 results in expression of multiple cytokines including type I IFN.
Given the importance of type I IFN in several malignancies including viral infections and cancer therapy, strategies that allow the specific activation of STING are of therapeutic interest.
WO 2014/093936 describes cyclic dinucleotide compounds that feature two purine nucleobases and two canonical 3,5′ phosphodiester or phosphorothioate moieties and induce STING-dependent cytokine production.
U.S. Pat. No. 7,709,458 describes cyclic dinucleotide compounds that feature two purine nucleobases and two canonical 3,5′ phosphodiester moieties and can be used to inhibit cancer cell proliferation or to increase cancer cell apoptosis, in particular the symmetrical bacterial CDN c-di-GMP.
U.S. Pat. No. 7,592,326 describes immunostimulatory cyclic dinucleotide compounds that feature two purine nucleobases and two canonical 3′,5′ phosphodiester moieties, in particular the symmetrical bacterial CDN c-di-GMP.
WO 2016/096174 and WO 2016/145102 describe cyclic dinucleotide compounds that feature two purine nucleobases and two canonical 3′,5′ phosphodiester or phosphorothioate moieties and induce STING-dependent cytokine production.
Bioorg. Med. Chem. Lett. 18 (2008) 5631-5634 describes immunostimulatory mono- and bis-phosphorothioate analogues of symmetrical bacterial CDN c-di-GMP.
WO 2014/189805 describes cyclic dinucleotide compounds that feature two purine nucleobases and at least one non-canonical 2′,5′ phosphodiester or phosphorothioate moiety and induce STING-dependent cytokine production.
WO 2015/185565 describes cyclic dinucleotide compounds that feature two purine nucleobases, one or two cyclopentane instead of ribose tetrahydrofurane rings and one non-canonical 2′,5′ phosphodiester moiety and modulate STING.
WO 2016/120305 describes cyclic dinucleotide compounds that feature two purine nucleobases, one ribose moiety in which the 2′-OH is replaced with a 2′-F and one non-canonical 2′,5′ phosphodiester moiety and modulate STING.
US 2014/0329889, WO 2014/099824, WO 2015/017652, Cell 154, 748-762 (2013), and Molecular Cell 51, 226-235 (2013) describe the cyclic dinucleotide 2′3′-cGAMP (cyclic [G(2′,5′)pA(3′,5′)p]) which features two purine nucleobases, one canonical 3,5′ and one non-canonical 2′,5′ phosphodiester moieties. Non-canonically linked 2′3′-cGAMP binds to human STING with higher affinity than canonically linked 3′3′-cGAMP or symmetrical bacterial c-di-GMP and induces type I interferon production.
Further cyclic dinucleotides with 2′,5′-2′,5′ or 2′,5′-3′,5′ connectivity are disclosed as STING agonists in WO 2017/027645 and WO 2017/027646, respectively.